POS0407 CHEMICALLY AND MECHANICALLY ACTIVATED PIEZO1 LEADS TO CHANGES IN THE EXPRESSION OF ECM-MODULATING FACTORS THAT DIFFER BETWEEN HEALTHY AND HUMAN OA CHONDROCYTES
Authors: B. Lohberger, B. Steinecker-Frohnwieser, V. Glanz, S. Toegel, L. Weigl
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is the most common degenerative joint disease that causes functional limitations in addition to pain and has become a major global health problem in recent decades. Meta-analysis of studies on patients with knee OA showed that physical exercise can function as a clinically relevant, effective intervention and non-drug treatment for reducing pain and improving physical activity in patients with OA [1]. In chondrocytes, the perception and transduction of mechanical signals leading to changes in [Ca<sup>2+]</sup><sub>i</sub> is orchestrated by mechanosensitive ion channels [2]. <h3>Objectives</h3> Piezo1 represents a mechanosensitive cation channel (MSC) that allows Ca<sup>2+</sup> influx in chondrocytes and acts as an important mechanotransducer that senses deleterious mechanical stresses (high strains) [3]. Numerous studies have shown that Ca<sup>2+</sup> regulation in conjunction with mechanical stimulation is crucial for the behaviour and function of chondrocytes and the balanced assembly of the ECM. The underlying mechanism could influence the expression profile as a consequence of mechanical stimulation. Differences in this regard between primary human chondrocytes isolated from knees of OA patients (pCHOA) and healthy chondrocytes could explain the altered sensitivity to mechanical stimuli in OA. <h3>Methods</h3> Mechanical stimulation of chondrocytes was performed by the use of the flexcell system whereas in parallel cells were chemically activated via different concentrations of the Piezo agonist Yoda1. Changes in expression were analysed by qPCR for metalloproteinases (MMP1, 3,13), inflammatory cytokines (IL6, IL8, IL4) and ECM relevant components (Col-I, Col-II, BMP2). The decreased expression of Yoda1 by siRNA knockdown was used to more clearly map the effect of MSC on ECM under mechanical stimulation. <h3>Results</h3> Chondrocytes responded to flexcell tension stimulation with decreased expression of MMP3 and IL6, whereas application of Yoda1 resulted in an opposite effect. In healthy chondrocytes the MMP expression was more enhanced than in OA chondrocytes whereas in both cell types the same reduction for TIMP-2 through the activation of Piezo1 was detected. Yoda1 increased IL6 and IL8 expression while IL4 was reduced. The knock-out of Piezo1 can partially reverse these effects. <h3>Conclusion</h3> Performing expression studies in the context of mechanical stimulation and targeting Piezo1 in OA and healthy chondrocytes may reveal OA-specific changes in mechanisms of mechanical signal transduction. Furthermore, this may provide further insight into the extent to which OA cells exhibit differential sensitization to mechanical signals. <h3>References</h3> [1]Sasaka, R., Honda, Y., Oga, S., et al. Effect of exercise and/or educational interventions on physical activity and pain in patients with hip/knee osteoarthritis: A systematic review with meta-analysis. <i>Plos One</i>. <b>2022,</b> 21;17(11),e0275591. [2]Zhang, K., Lifu, W., Liu Z., et al. Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis. <i>Channels (Austin</i>). <b>2021</b>, 15(1):339-359. [3]Du, G., Li, L., Zhang, X., et al. Roles of TRPV4 and Piezo Channels in Stretch-Evoked Ca2+ Response in Chondrocytes. <i>Exp. Biol. Med</i>. <b>2020</b>, 245(3), 180–189. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.